Bathelt Christine M, Ridder Lars, Mulholland Adrian J, Harvey Jeremy N
School of Chemistry and Centre for Computational Chemistry, University of Bristol, UK.
Org Biomol Chem. 2004 Oct 21;2(20):2998-3005. doi: 10.1039/B410729B. Epub 2004 Sep 28.
Cytochrome P450 enzymes play a central role in drug metabolism, and models of their mechanism could contribute significantly to pharmaceutical research and development of new drugs. The mechanism of cytochrome P450 mediated hydroxylation of aromatics and the effects of substituents on reactivity have been investigated using B3LYP density functional theory computations in a realistic porphyrin model system. Two different orientations of substrate approach for addition of Compound I to benzene, and also possible subsequent rearrangement pathways have been explored. The rate-limiting Compound I addition to an aromatic carbon atom proceeds on the doublet potential energy surface via a transition state with mixed radical and cationic character. Subsequent formation of epoxide, ketone and phenol products is shown to occur with low barriers, especially starting from a cation-like rather than a radical-like tetrahedral adduct of Compound I with benzene. Effects of ring substituents were explored by calculating the activation barriers for Compound I addition in the meta and para-position for a range of monosubstituted benzenes and for more complex polysubstituted benzenes. Two structure-reactivity relationships including 8 and 10 different substituted benzenes have been determined using (i) experimentally derived Hammett sigma-constants and (ii) a theoretical scale based on bond dissociation energies of hydroxyl adducts of the substrates, respectively. In both cases a dual-parameter approach that employs a combination of radical and cationic electronic descriptors gave good relationships with correlation coefficients R2 of 0.96 and 0.82, respectively. These relationships can be extended to predict the reactivity of other substituted aromatics, and thus can potentially be used in predictive drug metabolism models.
细胞色素P450酶在药物代谢中起着核心作用，其作用机制模型可为新药的药学研究与开发做出重大贡献。在一个逼真的卟啉模型体系中，利用B3LYP密度泛函理论计算研究了细胞色素P450介导的芳烃羟基化反应机制以及取代基对反应活性的影响。探讨了化合物I加成到苯上时底物接近的两种不同取向，以及可能的后续重排途径。限速步骤——化合物I加成到芳族碳原子上，是在双重态势能面上通过一个具有混合自由基和阳离子特征的过渡态进行的。结果表明，随后环氧化物、酮和酚产物的形成具有较低的势垒，特别是从化合物I与苯形成的类似阳离子而非类似自由基的四面体加合物开始。通过计算一系列单取代苯以及更复杂的多取代苯在间位和对位上化合物I加成的活化能垒，研究了环取代基的影响。分别使用（i）实验得出的哈米特σ常数和（ii）基于底物羟基加合物键解离能的理论标度，确定了包括8种和10种不同取代苯的两种结构-反应活性关系。在这两种情况下，采用自由基和阳离子电子描述符相结合的双参数方法都给出了良好的关系，相关系数R2分别为0.96和0.82。这些关系可以扩展到预测其他取代芳烃的反应活性，因此有可能用于预测性药物代谢模型。
